To prove that HDAC4 affects MDC biology in a cell non-autonomous manner, HDAC4 mKO and HDAC4fl/fl sera were withdrawn 4 days following injury, at the time of the HDAC4 maximal expression in skeletal muscle. Control MDCs were cultured with conditioned media by using HDAC4 mKO or HDAC4fl/fl sera, and MDC proliferation was evaluated after 24 h in growing condition, by Ki-67 immunofluorescence (Figure 5A). Quantification of Ki-67-positive cells revealed that
Renzini et al. HDAC4-Mediated, Non-autonomous Control of Myogenesis
FIGURE 2 |HDAC4 mKO mice exhibit delayed muscle regeneration.(A)Representative images of HDAC4 mKO and HDAC4fl/fltibialis anterior regenerating muscles, 1 week after injury. Scale bar = 50 micron.(B)Regenerating fiber CSA of HDAC4 mKO and HDAC4fl/flmice, 1 week after injury. Data are presented as median +/−SEM.n= 8 mice for genotype.∗p<0.05 by Student’st-test.(C)Morphometric analysis of the distribution of regenerating fiber cross-sectional area, 1 week after injury.n= 8 mice for genotype. Data are presented as average +/- SEM.∗p<0.05 by Student’st-test.(D)Gene expression of indicated myogenic markers in HDAC4 mKO and HDAC4fl/flmice, by real-time PCR, 4 days following injury. Data are presented as mean +/−SEM.n= 8 mice for genotype.∗p<0.05;
∗ ∗p<0.005 by Student’st-test.
HDAC4 mKO sera reduced the MDC proliferating cell number, compared to HDAC4fl/flsera (Figure 5B), data also confirmed by the quantification of the MDCs (Figure 5C).
To investigate if the reduction in MDC proliferation influences their terminal differentiation, control MDC were induced to differentiate, by mean of conditioned media with HDAC4 mKO or HDAC4fl/fl mouse sera, as control.
HDAC4 mKO sera significantly reduced also MDC terminal differentiation and fusion, as assessed by immunofluorescence for MHC and quantification of the differentiation and fusion indexes (Figures 5D,E). Quantification of MDCs, after 3 days of differentiation, confirmed a significant reduction in the MDC number upon HDAC4 mKO serum treatment with respect to controls (Figure 5F). These data demonstrate that HDAC4 mediates the production and release of circulating factors able to negatively affect MDC proliferation and differentiation.
DISCUSSION
Numerous studies clarified that MDC biology is controlled by cell-autonomous and non-autonomous cues, as well as by
epigenetic mechanisms (Boonen and Post, 2008; Moresi et al., 2015). In this study, we investigated which functions HDAC4 plays during muscle regeneration. HDAC4 is a stress-responsive epigenetic factor known to regulate multiple responses in skeletal muscle, including satellite cells biology upon injury (Moresi et al., 2010; Choi et al., 2014; Marroncelli et al., 2018). We found HDAC4 to be induced to a significant extent in skeletal muscle upon injury, in line with previous findings (Choi et al., 2014), with the expression peaking in the early phases of regeneration, suggesting that HDAC4 mediates skeletal muscle response to injury. To dissect the HDAC4 biological functions in skeletal muscle, excluding SCs in the early phases of differentiation, we generated HDAC4 mKO mice, in which HDAC4 deletion occurs upon myogenin expression. HDAC4 mKO mice do not show skeletal muscle abnormalities at baseline (Moresi et al., 2010;Pigna et al., 2018).
However, following injury, deletion of HDAC4 in skeletal muscle significantly hampered muscle regeneration. When HDAC4 deletion occurs in myogenin-positive cells, MDCs efficiently proliferate and differentiate in vitro, differently from HDAC4 KO SCs, having compromised expansion and differentiation in a cell-autonomous manner (Choi et al., 2014; Marroncelli
Renzini et al. HDAC4-Mediated, Non-autonomous Control of Myogenesis
FIGURE 3 |HDAC4 mKO mice show impaired muscle regeneration.(A)Representative images of HDAC4 mKO and HDAC4fl/fltibialis anterior regenerating muscles, 2 weeks after injury. Scale bar = 50 micron.(B)Regenerating fiber CSA of HDAC4 mKO and HDAC4fl/flmice, 2 weeks after injury. Data are presented as median +/−SEM.n= 8 mice for genotype.∗ ∗p<0.02 by Student’st-test.(C)Morphometric analysis of the distribution of regenerating fiber cross-sectional area, 2 weeks after injury.n= 8 mice for genotype. Data are presented as average +/- SEM.∗p<0.05 by Student’st-test.(D)Representative images of HDAC4 mKO and HDAC4fl/fltibialis anterior regenerating muscles, 1 month after injury. Scale bar = 50 micron.(E)Regenerating fiber CSA of HDAC4 mKO and HDAC4fl/flmice, 1 month after injury.n= 8 mice for genotype. Data are presented as median +/−SEM.∗p<0.05 by Student’st-test.(F)Morphometric analysis of the distribution of regenerating fiber cross-sectional area, 1 month after injury.n= 5 mice for genotype. Data are presented as average +/- SEM.∗p<0.05 by Student’st-test.
et al., 2018). Despite MDC ability to differentiate in vitro, compromised muscle regeneration in HDAC4 mKO mice indicates that, in the injured muscle, HDAC4 influences MDCs
behavior, evidencing novel HDAC4 cellular functions depending on the timing and/or the cell sub-type where this enzyme is expressed.
Renzini et al. HDAC4-Mediated, Non-autonomous Control of Myogenesis
FIGURE 4 |HDAC4 mKO MDCs efficiently proliferate and differentiatein vitro.(A)Representative pictures of immunofluorescence for Ki-67 in HDAC4 mKO and HDAC4fl/flMDCs, after 24 h in growth media. Scale bar = 50µm.(B)Quantification of the proliferating Ki-67+cells, over the total cell number. Data are presented as mean +/– SEM.n= 3 mice for genotype.(C)Quantification of HDAC4 mKO and HDAC4fl/flMDC number, after 24 h in growth media. Data are presented as mean +/– SEM.n= 3 mice for genotype.(D)Representative pictures of immunofluorescence for MHC in HDAC4 mKO and HDAC4fl/flMDCs, after 3 days in differentiation medium. Scale bar = 50µm.(E)Quantification of the differentiation and fusion indexes of HDAC4 mKO and HDAC4fl/flMDCs. Data are presented as mean +/–
SEM.n= 3 mice for genotype.
Interestingly, the decrease of the expression level of the SCs marker Pax7 4 days after injury indicates a deficit in either SC number or proliferation. The paired box transcription factor Pax7 is the master regulator of SC (Seale et al., 2000), required for SC function in adult skeletal muscle. Indeed, upon Pax7 deletion, SCs exhibit cell-cycle arrest and dysregulation of MRFs, muscles resulted smaller and muscle regeneration was severely impaired (Oustanina et al., 2004; Kuang et al., 2006; Relaix et al., 2006). Since HDAC4 mKO MDCs were able to proliferate or differentiate efficiently in vitro, soluble factors likely mediate the reduction of Pax7 expression in regenerating HDAC4 mKO muscles.
By using culture media conditioned with sera from injured HDAC4 mKO or HDAC4fl/flmice, we proved that HDAC4 does mediate the secretion of circulating factors able to influence MDC proliferation and differentiation. Numerous environmental factors regulate adult myogenesis during regeneration. Growth factors released from injured myofibers strictly regulate the activation of quiescent SC (Furuichi and Fujii, 2017). SC proliferation is supported by mitogens such as FGF and insulin-like growth factor (IGF), which get up-regulated in skeletal muscle after injury (Guthridge et al., 1992;Bischoff and Heintz, 1994). Furthermore, activated SCs secrete miRNAs - containing exosomes, which in turn modulate SC proliferation and
differentiation (Harding and Velleman, 2016). SC differentiation is strictly influenced by secreted factors as well. For instance, insulin-like growth factor 1 (IGF1) and interleukin 15 (IL-15) secretion is induced after membrane damage or during exercise, these myokines promote SC differentiation and contributes to muscle hypertrophy by enhancing protein synthesis (DeVol et al., 1990; Adams, 2002; Quinn et al., 2002; Furmanczyk and Quinn, 2003). Among soluble factors acting on SC differentiation, several inflammatory cytokines are known to inhibit this process. TNF-α and interleukin 1 (IL-1) are inflammatory mediators of muscle wasting and interfere with the expression of myogenic factors in differentiating myoblasts, by activating the nuclear factor – kappa beta (NFkβ) and caspases (Langen et al., 2001; Moresi et al., 2008, 2009). In addition to inhibit SC activation and self-renewal, numerous secreted factors negatively affect also SC differentiation and fusion, among them myostatin and growth differentiation factor-11 (GDFfactor-11) (TGFβsuperfamily’s members) are known to hamper muscle regeneration by inhibiting SC activity on distinct phases during myogenesis (Reisz-Porszasz et al., 2003;Egerman et al., 2015).
HDACs have been shown to regulate soluble factors in different cell types. In neuronal and glial cells, the release of brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 1 (FGF1) is mediated by HDACs (Hossain
Renzini et al. HDAC4-Mediated, Non-autonomous Control of Myogenesis
FIGURE 5 |HDAC4 mKO serum negatively affects control MDC proliferation and differentiation.(A)Representative pictures of immunofluorescence for Ki-67 in control MDCs, after 24 h in conditioned media with sera from either injured HDAC4 mKO or HDAC4fl/flmice. Scale bar = 50µm.(B)Quantification of the proliferating Ki-67+cells, over the total cell number. Data are presented as mean +/– SEM.n= 6 mice for genotype.∗p<0.05 by Student’st-test.(C)Quantification of MDC number cultured with sera from either injured HDAC4 mKO or HDAC4fl/flmice. Data are presented as mean +/– SEM.n= 6 mice for genotype.∗p<0.05 by Student’st-test.(D)Representative pictures of immunofluorescence for MHC in control MDCs cultured with conditioned media with sera from either HDAC4 mKO or HDAC4fl/flinjured mice, after 3 days in differentiation medium. Scale bar = 100µm.(E)Quantification of the differentiation and fusion indexes of control MDCs cultured with sera from either injured HDAC4 mKO or HDAC4fl/flmice, after 3 days in differentiation medium. Data are presented as mean +/– SEM.n= 6 mice for genotype.∗ ∗p<0.005 by Student’st-test.(F)Number of control MDCs cultured with sera from either injured HDAC4 mKO or HDAC4fl/flmice, after 3 days in differentiation medium. Data are presented as mean +/– SEM.n= 6 mice for genotype.∗ ∗p<0.005 by Student’st-test.
et al., 2018), as well as in fibroblasts the production of several proinflammatory cytokines/chemokines (Li et al., 2011), thus contributing to chronic inflammatory processes. Moreover, HDACs modulate IL-4 expression and secretion in mast cells and monocyte-derived DCs (moDCs) (López-Bravo et al., 2013; Nakamaru et al., 2015). In addition to its classical roles, new evidence links HDACs and soluble factors. For instance, cytoplasmic protein acetylation/deacetylation balance has been involved in extracellular vesicles content and release
in colon cancer cells (Li et al., 2016; Chao et al., 2017).
In skeletal muscle, the expression of several soluble factors, such as TGF-β and follistatin, are modulated by HDAC4 during myogenesis (Sun et al., 2010; Winbanks et al., 2011).
Moreover, HDAC4 promotes skeletal muscle reinnervation via the release of FGF binding protein 1 (Williams et al., 2009).
A preclinical study in a murine Duchenne Muscular Dystrophy model demonstrated that Givinostat, a class I and
Renzini et al. HDAC4-Mediated, Non-autonomous Control of Myogenesis
II HDAC inhibitor, improves skeletal muscle regeneration by reducing fibrotic and adipose tissues (Mozzetta et al., 2013).
Similarly, trichostatin A (TSA), another class I-II HDAC inhibitor, promotes skeletal muscle regeneration by targeting fibro-adipogenic cells and inducing the expression and the release of follistatin, a pro-myogenic soluble factor identified as a central mediator in myoblast recruitment and fusion (Iezzi et al., 2004;
Mozzetta et al., 2013). Our results are in apparent contrast with the findings of previous studies obtained by administering HDAC inhibitors during muscle regeneration. However, different experimental conditions could reconcile such discrepancy. In those studies, muscle regeneration was improved by daily systemic administration of class I and II HDAC inhibitors after injury, which is different from our study exploiting HDAC4 mKO mice, a tissue-specific KO mouse bringing the genetic deletion at embryonic stage E8.5 of one member of the class IIa HDACs.
CONCLUSION
The present study sheds further light on multiple HDAC4 functions in skeletal muscle following injury stress. HDAC4 not only promotes SC replenishment and differentiation in a cell-autonomous manner via the epigenetic regulation of gene transcription but also influences MDC proliferation and differentiation via muscle derived-soluble factors. These findings should be considered when administering class I-II HDAC inhibitors to treat muscular diseases.
AUTHOR CONTRIBUTIONS
AR, NM, and CN performed the experiments. VM and SA conceived the project and analyzed the data. All authors contributed to critical analysis. AR, VM, and SA wrote the manuscript and all authors approved the final manuscript for publication.
FUNDING
This study has been funded by Ricerca finalizzata (GR-2010-2311055) from the Italian Ministry of Health and partially supported by Sapienza research projects 2016 (SapMedi2016) and 2017 (RM11715C78539BD8).
ACKNOWLEDGMENTS
We are grateful to Carla Ramina for her technical assistance.
We are grateful to Prof. Eric N Olson and Rhonda Bassel-Duby (University of Texas Southwestern Medical Center, Dallas, TX, United States) for the mouse line and the scientific advice. The MF 20 monoclonal antibody was developed by D. A. Fishman and obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA, United States, 52242.
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